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Li, Xian,Park, Soon Jin,Jin, Fansi,Deng, Yifeng,Yang, Ju Hye,Chang, Jae-Hoon,Kim, Dong-Young,Kim, Jung-Ae,Lee, Youn Ju,Murakami, Makoto,Son, Kun Ho,Chang, Hyeun Wook Pergamon Press 2018 Biochemical pharmacology Vol.152 No.-
<P><B>Abstract</B></P> <P>AMP-activated protein kinase (AMPK) and its upstream mediators liver kinase B1 (LKB1) and sirtuin 1 (Sirt1) are generally known as key regulators of metabolism. We have recently reported that the AMPK pathway negatively regulates mast cell activation and anaphylaxis. Tanshinone IIA (Tan IIA), an active component of <I>Salvia miltiorrhiza</I> extract that is currently used for the treatment of cardiovascular and cerebrovascular diseases, shows anti-diabetic activity and improves insulin resistance in <I>db/db</I> mice through activation of AMPK. The aim of this study was to evaluate the anti-allergic activity of Tan IIA <I>in vivo</I> and to investigate the underlying mechanism <I>in vitro</I> in the context of AMPK signaling. The anti-allergic effect of Tan IIA was evaluated using mouse bone marrow-derived mast cells (BMMCs) from <I>AMPKα2</I> <SUP>−/−</SUP> or <I>Sirt1</I> <SUP>−/−</SUP> mice, or BMMCs transfected with siRNAs specific for AMPKα2, LKB1, or Sirt1. <I>AMPKα2</I> <SUP>−/−</SUP> and <I>Sirt1</I> <SUP>−/−</SUP> mice were used to confirm the anti-allergic effect of Tan IIA in anaphylaxis <I>in vivo</I>. Tan IIA dose-dependently inhibited FcεRI-mediated degranulation and production of eicosanoids and cytokines in BMMCs. These inhibitory effects were diminished by siRNA-mediated knockdown or genetic deletion of AMPKα2 or Sirt1. Moreover, Tan IIA inhibited a mast cell-mediated local passive anaphylactic reaction in wild-type mice, but not in <I>AMPKα2</I> <SUP>−/−</SUP> or <I>Sirt1</I> <SUP>−/−</SUP> mice. In conclusion, Tan IIA suppresses FcεRI-mediated mast cell activation and anaphylaxis through activation of the inhibitory Sirt1-LKB1-AMPK pathway. Thus, Tan IIA may be useful as a new therapeutic agent for mast cell-mediated allergic diseases.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
( Xian Li ),( Ju Hye Yang ),( Ye Jin ),( Fansi Jin ),( Dong Young Kim ),( Jae Hoon Chang ),( Jung Ae Kim ),( Jong Keun Son ),( Tae Chul Moon ),( Kun Ho Son ),( Hyeun Wook Chang ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
Ethnopharmacological relevance: 15,16-Dihydrotanshinone I (DHT-I), isolated from the dried root of Salvia miltiorrhiza Bung, which is traditionally used to treat cardiovascular and inflammatory diseases agent in Chinese medicine. DHT-I has been reported to have a broad range of biological activities, including antibacterial activity, and has been used to treat circulatory disorders, hepatitis, inflammation, cancer, and neurodegenerative diseases. Aim of the study: The aim of this study was to evaluate the anti-allergic inflammatory effects of DHT-I on degranulation and on the generation of eicosanoids, such as, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4), in IgE/Ag-stimulated bone marrow-derived mast cells (BMMCs). Materials and methods: The anti-allergic inflammatory activity of DHT-I was evaluated using BMMCs. The effects of DHT-I on mast cell activation were investigated by following degranulation and eicosanoid generation using ELISA and immunoblotting and immunoprecipitation techniques. Results: DHT-I at a concentration of 20 μM markedly inhibited degranulation and the generation of PGD2 and LTC4 in IgE/Ag-stimulated BMMCs (about 90% inhibitions, respectively). Analyses of FcεRI-mediated signaling pathways demonstrated that DHT-I inhibited the phosphorylations of spleen tyrosine kinase (Syk) and linker for activation of T cells (LAT), and inhibited downstream signaling process, including [Ca2þ]i mobilization induced by the phosphorylation of phospholipase Cγ1 (PLCγ1), and the activations of mitogen-activated protein kinases (MAPKs) and the Akt-nuclear factor-κB (NF-κB) pathway. Conclusions: DHT-1 inhibits the release of allergic inflammatory mediators from IgE/Ag-stimulated mast cells by suppressing a FcεRI-mediated Syk-dependent signal pathway. This result suggests DHT-I offers a novel developmental basis for drugs targeting allergic inflammatory diseases. & 2015 Elsevier Ireland Ltd. All rights reserved.
( Min Kyun Na ),( Yong Tae Jeong ),( Xian Li ),( Fansi Jin ),( Seung Lark Hwang ),( Geum Jin Kim ),( Ju Hye Yang ),( Young Chae Chang ),( Dong Soo Kim ),( Cheorl Ho Kim ),( Hyeun Wook Chang ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-
The effect of butanol extracts of the skin of Anguilla japonica (BESA) on endoplasmic reticulum (ER) stress-induced insulin resistance in L6 myotubes was investigated. Western blotting revealed that BESA increased phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, and stimulated glucose uptake in L6 myotubes. Stimulation of AMPK and glucose uptake by BESA were significantly (p<0.05) reduced by siRNA LKB1 or siRNA AMPK, compared with controls, suggesting that enhanced glucose uptake by BESA was predominantly accomplished via an LKB1-mediated AMPK activation pathway. In addition, BESA effectively reduced phosphorylation of ER stress markers, RNA-activated protein kinaselike ER resident kinase, JNK, and significantly (p<0.01) increased glucose uptake via AMPK activation in tunicamycin-treated L6 myotubes, compared with controls. Improvement of insulin sensitivity under ER stress conditions by BESA is predominantly accomplished via an LKB1- AMPK-dependent pathway.
( Chang Su Lee ),( Hyun Ji Cho ),( Yun Jeong Jeong ),( Jae Moon Shin ),( Kwan Kyu Park ),( Yoon Yub Park ),( Young Seuk Bae ),( Il Kyung Chung ),( Mihyun Kim ),( Cheorl Ho Kim ),( Fansi Jin ),( Hyeun 영남대학교 약품개발연구소 2016 영남대학교 약품개발연구소 연구업적집 Vol.26 No.-
Isothiocyanates (ITCs) derived from cruciferous vegetables, including benzyl isothiocyanate (BITC), phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit preventative effects against various types of cancers. Yet, the inhibitory effects of ITCs on C6 glioma cell invasion and migration have not been reported. Thus, we aimed to analyze lTC-regulated MMP-9 activation, a crucial enzyme of cancer metastasis that degrades the extracellular matrix, in C6 glioma cells to investigate the inhibitory effects on cancer invasion and migration by ITCs. In the present study, we found that ITCs specifically suppressed PMA-induced MMP-9 secre-tion and protein expression. The inhibitory effects of ITCs on PMA-induced MMP-9 expression were found to be associated with the inhibition of MMP-9 transcription levels through suppression of nuclear translocation of NF-KB and activator protein-I (AP-l). It was also confirmed that ITCs decreased MMP-9-mediated signaling such as FAK and JNK, whereas they had no effect on the phosphorylation of ERK and p38. Moreover, wound-healing and Transwell invasion assays showed that ITCs inhibited the migration and invasion of C6 glioma cells. These results suggest that ITCs could be potential agents for the prevention of C6 glioma cell migration and inva-sion by decreasing FAK/JNK-mediated MMP-9 expression.